12-57766019-C-T

Variant names:

• chr12-57766019-C-T
• rs28934605
• NM_000785.4:c.374G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000785.4(CYP27B1):​c.374G>A​(p.Gly125Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,419,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). ClinVar reports functional evidence for this variant: "SCV004037925: The variant protein had no 1alpha-hydroxylase activity (Kitanaka_1998). PMID:9486994". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G125V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CYP27B1 NM_000785.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.31
• Publications: 9 publications found

Genes affected

CYP27B1 (HGNC:2606): (cytochrome P450 family 27 subfamily B member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The protein encoded by this gene localizes to the inner mitochondrial membrane where it hydroxylates 25-hydroxyvitamin D3 at the 1alpha position. This reaction synthesizes 1alpha,25-dihydroxyvitamin D3, the active form of vitamin D3, which binds to the vitamin D receptor and regulates calcium metabolism. Thus this enzyme regulates the level of biologically active vitamin D and plays an important role in calcium homeostasis. Mutations in this gene can result in vitamin D-dependent rickets type I. [provided by RefSeq, Jul 2008]

CYP27B1 Gene-Disease associations (from GenCC):

• vitamin D-dependent rickets, type 1A

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• vitamin D-dependent rickets, type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004037925: The variant protein had no 1alpha-hydroxylase activity (Kitanaka_1998). PMID: 9486994
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-57766019-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3339277.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 12-57766019-C-T is Pathogenic according to our data. Variant chr12-57766019-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1659.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000785.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP27B1	NM_000785.4	MANE Select	c.374G>A	p.Gly125Glu	missense	Exon 2 of 9	NP_000776.1	O15528

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP27B1	ENST00000228606.9	TSL:1 MANE Select	c.374G>A	p.Gly125Glu	missense	Exon 2 of 9	ENSP00000228606.4	O15528
	CYP27B1	ENST00000713544.1		c.374G>A	p.Gly125Glu	missense	Exon 2 of 9	ENSP00000518840.1	A0AAA9YHN9
	CYP27B1	ENST00000713545.1		c.374G>A	p.Gly125Glu	missense	Exon 2 of 9	ENSP00000518841.1	A0AAA9YHZ6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1419816 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 703274

African (AFR) AF: 0.00 AC: 0 AN: 32860

American (AMR) AF: 0.00 AC: 0 AN: 39076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25392

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38174

South Asian (SAS) AF: 0.00 AC: 0 AN: 81556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4668

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1095950

Other (OTH) AF: 0.00 AC: 0 AN: 58922

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Vitamin D-dependent rickets, type 1A (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.86		Gain of catalytic residue at T128 (P = 0.0555)
MVP		0.94
MPC		1.5
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		-0.016	Neutral
Varity_R		0.98
gMVP		0.93
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28934605; hg19: chr12-58159802;